This proposal continues studies in 4 main areas: I. Mechanisms Governing Progression of Diabetic Glomerular Disease: Contributions of Altered Hemodynamics, Permselectivity and Mesangial Function. Micropuncture, fractional dextran/dextran sulfate clearances and morphologic/morphometric techniques will be used to study the factors that a) underlie the progression of diabetic renal disease; b) interfere with the progression of renal disease (prostaglandin inhibitors, anticoagulants, etc.); c) alter permselectivity and mesangial function; d) underlie the glomerular hemodynamic response (hyperfiltration) to growth hormone, glucagon and somatostatin. II. Examine the Role of Hemodynamic Factors in Mediating Extrarenal Microangiopathy. Studies in this area will involve assessment of peripheral transcapillary escape rates of 131-I-albumin, neutral and charged dextrans and evaluation of the role of chronic capillary hydraulic pressure elevation on peripheral and retinal capillary structure and function. III. Biochemical Abnormalities Underlying Diminished Vascular Responsiveness to Vasoactive Agonists in Diabetes. Studies will examine mechanisms regulating glomerular, mesentery artery smooth muscle and adrenal angiotensin II receptor density; evaluate the selective effects of insulin lack, hyperglycemia, hyperglucagonemia and metabolic acidosis on these mechanisms, and determine whether glomerular alpha-adrenoreceptors are also disturbed in diabetes. IV. Mechanisms of Control of Ion and Fluid Transport Across Renal and Intestinal Brush Border Membrane Vesicles Derived from Diabetic Rats. The influences of diabetes and of insulin therapy on Na+-H+ countertransport and other Na+-solute cotransports will be studied as will the role of altered membrane fluidity and Na+-K+ ATPase activity induced by the diabetic state. Studies are aimed at elucidating the mechanisms underlying common renal, fluid, electrolyte and systemic microangiopathic disorders encountered in diabetes mellitus.